Journal article
A mathematical model of the phosphoinositide pathway
- Abstract:
- Phosphoinositides are signalling lipids that constitute a complex network regulating many cellular processes. We propose a computational model that accounts for all species of phosphoinositides in the plasma membrane of mammalian cells. The model replicates the steady-state of the pathway and most known dynamic phenomena. Sensitivity analysis demonstrates model robustness to alterations in the parameters. Model analysis suggest that the greatest contributor to phosphatidylinositol 4,5-biphosphate (PI(4,5)P2) production is a flux representing the direct transformation of PI into PI(4,5) P2, also responsible for the maintenance of this pool when phosphatidylinositol 4-phosphate (PI(4) P) is decreased. PI(5)P is also shown to be a significant source for PI(4,5)P2 production. The model was validated with siRNA screens that knocked down the expression of enzymes in the pathway. The screen monitored the activity of the epithelium sodium channel (ENaC), which is activated by PI(4,5)P2. While the model may deepen our understanding of other physiological processes involving phosphoinositides, we highlight therapeutic effects of ENaC modulation in Cystic Fibrosis (CF). The model suggests control strategies where the activities of the enzyme phosphoinositide 4-phosphate 5-kinase I (PIP5KI) or the PI4K + PIP5KI + DVL protein complex are decreased and cause an efficacious reduction in PI(4,5)P2 levels while avoiding undesirable alterations in other phosphoinositide pools.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 3.0MB, Terms of use)
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- Publisher copy:
- 10.1038/s41598-018-22226-8
Authors
- Publisher:
- Nature Publishing Group
- Journal:
- Scientific Reports More from this journal
- Volume:
- 8
- Issue:
- 1
- Pages:
- 3904
- Publication date:
- 2018-03-02
- Acceptance date:
- 2018-02-19
- DOI:
- EISSN:
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2045-2322
- ISSN:
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2045-2322
- Pmid:
-
29500467
- Language:
-
English
- Keywords:
- Pubs id:
-
pubs:828820
- UUID:
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uuid:2b19a5b5-1f0a-4fb0-b9b5-883f063b1c17
- Local pid:
-
pubs:828820
- Source identifiers:
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828820
- Deposit date:
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2018-08-28
- ARK identifier:
Terms of use
- Copyright holder:
- Uliyakina et al
- Copyright date:
- 2018
- Notes:
- © The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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